Summary 1) The collaboration with the Brazilian national reference center for multidrug resistant tuberculosis (MDR TB) has allowed us to more fully study epidemiologic patterns and clinical features of nontuberculous mycobacterial pulmonary disease in other countries. These patients represent primarily patients referred from the state of Rio de Janeiro. We found that among persons referred to the Centro de Referencia Prof Helio Fraga (CRPHF), diagnosis of PNTM has been increasing over the last 18 years. In this group 72% met criteria for pulmonary disease as defined by the American Thoracic Society (ATS), and 34% had no underlying diagnosis. Most patients (58%) reported a history of prior TB treatment; however, this treatment was based on a positive smear only, without microbiologic confirmation of Mycobacterium tuberculosis, thus, it is likely that these patients were not truly infected with M. TB. Based on hsp65 PCR ascertainment, infection with Mycobacterium kansasii species predominated, in contrast to the United States, where Mycobacterium avium predominates. Treatment outcome varied significantly by infecting species, with the highest cure rate (71%) observed among patients infected with M. kansasii, followed by those infected with MAC (58%). Among those infected with M. kansasii, cure rates did not vary by the presence of cavitary disease. In contrast, among those infected with M. avium or M. abscessus, patients with noncavitary disease were twice as likely to be cured (defined as at least three consecutive respiratory specimens negative for NTM during 12 consecutive months). In summary, the increasing identification of NTM among patients referred for treatment of MDR TB in this area of Brazil highlights the need for improved diagnostic capacity and increased awareness among clinicians treating patients with suspected tuberculosis. 2) Persons with cystic fibrosis (CF) are at high risk of nontuberculous mycobacterial (NTM) infection, with treatment requiring prolonged multi-drug regimens that include macrolides. While macrolides, specifically azithromycin, are used in the management of CF patients with chronic Pseudomonas, macrolide-resistant NTM infections are of growing concern. Further, a recent study suggested a possible link between long-term macrolide use in CF patients with an increased NTM infection rate, specifically theorizing that long-term azithromycin use may predispose CF patients to infection with M. abscessus by facilitating mycobacterial survival through the blocking of intracellular autophagy, the immune response needed to clear these infections. Clarifying the relationships between long-term macrolide therapy and NTM infections by species is vital for providing improved NTM treatment and prevention recommendations for the CF population, and provides insights into treatment for the non-CF population as well. The CF Patient Registry (CFPR) collects extensive data annually on >90% of all U.S. CF patients, including detailed mycobacterial data starting in 2010. We obtained data from the 2011 Cystic Fibrosis Patient Registry to further study patterns of NTM among CF patients and further address these issues. The 2011 CFPR included 27,112 patients; 5,403 (20%) were cultured for mycobacteria in 2010-2011 and met all inclusion criteria. Of these, 191 (4%) were NTM-positive in 2011 only (incident cases), while 5,212 (96%) were NTM-negative in both 2010 and 2011 (controls). Among the cases, 122 (64%) were culture-positive for Mycobacterium avium complex (MAC) and 69 (36%) for M. abscessus. Azithromycin use in 2010 was less frequently reported among MAC cases (57%; OR=0.7, p<0.05) and M. abscessus cases (51%; OR=0.5, p<0.01) than in controls (66%). Among adolescents and adults, patients with the greatest number of years on chronic macrolides were the least likely to develop incident NTM in 2011 (p<0.01). In summary, incident NTM cases were significantly less likely to have had prior long-term azithromycin use. 3) Women over the age of 50 who lack antecedent structural lung damage have emerged as a growing population afflicted with pulmonary nontuberculous mycobacteria (PNTM). A common body morphology amongst these women, who are often tall and lean with scoliosis, pectus excavatum (PE), and mitral valve prolapse (MVP), points to a possible genetic basis for susceptibility to PNTM. Exploration of these traits in family members of PNTM patients provides evidence for the hypothesis that genetic factors modify disease susceptibility. We conducted a comprehensive review of families with PNTM designed to identify a familial phenotype of disease. Probands included in our study were adult patients who met diagnostic criteria for PNTM and were enrolled in a natural history of mycobacterial disease protocol at the National Institutes of Health. Probands with other known underlying structural lung diseases or characterized immunodeficiency were excluded. All probands were contacted to construct family pedigrees extending to first- and second-degree relatives. Probands were asked to report the following in all members of the pedigree: current or past diagnosis of PNTM, bronchiectasis, MVP, scoliosis, and PE. 383 patients were enrolled in the natural history protocol, of whom 109 probands met inclusion criteria. This population comprised 2285 first- and second-degree relatives with an average of 21 family members per proband. The majority of probands were white females with an average age of 66.7 years. The most common mycobacterial species was M. avium complex, followed by M. abscessus and M. fortuitum. Sixty-three (57.8%) patients had scoliosis, 15 (13.8%) had echocardiographic evidence of MVP, and 4 (3.7%) had radiographic evidence of PE by the Haller index. Of 109 probands, 14 (12.8%) reported having at least 1 other first- or second-degree relative diagnosed with PNTM. In addition, 13 (11.9%) probands reported bronchiectasis and 21 (19.2%) probands reported scoliosis in at least 1 relative. MVP was found in 7 (6.4%) families and PE in 6 (5.5%) families. 23 relatives exhibited just scoliosis, 14 exhibited just MVP, and 12 exhibited just PE. 2 relatives exhibited scoliosis and MVP together and 1 relative exhibited MVP and PE together. The proportion of family members with associated traits greatly exceeds that found in general comparable unrelated populations. The genetic underpinnings of this familial syndrome remain undetermined. The triad of scoliosis, MVP, and PE points strongly to a Marfan-like syndrome, although it should be noted that none of our probands met diagnostic criteria for Marfan syndrome. Marfan syndrome is known to be associated with bronchiectasis. In addition, other connective tissue diseases such as congenital contractural arachnodactyly have been associated with PNTM infection. Involvement of the transforming growth factor beta pathway, alterations in which account for many connective tissue diseases, could potentially explain the marked similarities in body morphotype between the families in our cohort and the connective tissue disease population.This study is the first to show a familial clustering of traits related to PNTM infections in otherwise unaffected relatives. The higher than expected prevalence of PNTM, bronchiectasis, scoliosis, MVP, and PE strongly supports a genetic basis for at least some cases of PNTM.